Genetic factors contribute to the development of alcohol dependence (AD). Substantial progress has been made in identifying specific risk genes, but currently known well-supported loci still account for only a small proportion of the overall disease risk. In the last iteration of this project, we recruited and rigorously assessed ~2000 AD subjects and relatives, with oversampling of African Americans (AAs); we also contributed to the understanding of AD risk though candidate gene studies of AD and related phenotypes, and gene-by-environment interaction involving AD risk (with mapping by admixture linkage disequilibrium studies currently in progress). It is widely appreciated that whole genome association studies (WGAS) have the potential to reveal more risk loci. The quality of such studies is always limited by the quality of the available phenotypic assessments; our investment in state-of-the-art phenotypic characterization has resulted in a sample that should be an outstanding one to probe for novel risk loci by this method. In the present application, we propose to recruit an additional 1250 AD subjects (primarily AAs and EAs); and to conduct a WGAS study of 2000 European American AD subjects and 4000 controls in two waves of 1000 affecteds and 2000 controls; and follow-up studies of implicated loci (in an expanded sample of already-collected AD subjects and a large sample of German AD affecteds and controls) via SNP genotyping and deep sequencing. Additionally, we will study high resolution copy number variation (CNV) in a subsample of AD subjects. When both waves of the study have been completed, we will be able to study subphenotypes within the sample (e.g., family history positive vs. negative, AD with or without other substance dependence comorbidity), both in case-only comparisons and in comparison to control subjects. A companion WGAS application with already-collected AA samples has been contingently-approved by CIDR for genotyping. The current project could provide the opportunity for instructive comparison of risk loci between AA and EA populations, with the potential to isolate associated regions. This project has the potential to contribute substantially to our growing knowledge of genetic risk factors for AD and related traits.